DESCRIPTION (Reproduced verbatim from the applicant's abstract): This competing renewal application will extend the applicant's studies on the relationship of the a2M receptor/ LRP to AD. LRP, a large multifunctional receptor with multiple ligand binding domains, is the major neuronal receptor for apolipoprotein E (apoE), a2M, and the KPI-containing forms of the APP, all implicated in the pathophysiology of AD by both biochemical and genetic evidence. Our overarching hypothesis is that Abeta deposition is central to AD, and that LRP is in a critical position to influence the balance of Abeta generation and clearance. Both apoE and a2M form stable complexes with Abeta. Aim 1 tests the hypothesis that apoE/Abeta and a2M/Abeta complexes are cleared and that this clearance is via LRP. We will determine the specific domains on LRP that mediate these processes. Aim 2 explores our recent observation that LRP binds and internalizes full length APP, and that blocking this endocytic process decreases Abeta generation and secretion. The discovery that the LRP intracellular domain binds the adapter protein Fe65, a protein which is known to form a complex with the intracellular domain of APP, also implicates APP-LRP complex formation as being important in APP trafficking and potentially Abeta generation. We have also found that LRP undergoes PKC-mediated serine phosphorylation, and will test the hypotheses that this affects LRP trafficking, or interactions with Fe65 or APP. Aim 3 tests the hypothesis, based on new preliminary data, that LRP may serve a role both as an endocytic receptor and as a novel type of signaling receptor in neurons. We have observed that activated a2M induces a RAP-blockable, calcium response in neurons (but not non-neuronal cells), and will characterize this calcium response. Ligand-competent a2M also induces an increase in LRP amount and cell surface LRP; our working hypothesis is that the amount of cell surface LRP is regulated in part by this calcium response. The proposed studies will continue a highly productive and long standing collaboration among investigators at the Massachusetts General Hospital and the American Red Cross in order to pursue new exciting leads which impact our understanding of pathophysiologic mechanisms in AD, and which: will lead to additional insight in the neurobiology of LRP.